Using two strain combinations in a heterotopic cardiac allograft model in rats, the applicants have shown that the donor specific transfusion (DST) effect on prolongation of graft survival can be augmented by thymopentin (TP-5). This effect is dose dependent and seen only when the TP-5 is given at the time of the DST. The DST effect can also be augmented by multiple transfusions and is further augmented by the administration of TP-5 with each transfusion. Additionally, both high fatty acid in the diets and 16,16 dimethyl PGE2 augmented the DST effect. When a small dose of cyclosporine A was given for only 30 days during the posttransplant period, multiple DSTs with or without low dose TP-5 resulted in indefinite allograft survival in many animals. The present study will determine the optimal conditions for augmentation of the donor specific transfusion effect. Experiments will be performed 1) to determine the optimal dosage of TP-5 for potentiation of the DST effect, 2) to determine the ability of high lipid diets to potentiate the TP-5-DST effect, 3) to determine the ability of other immunomodulators (muramyl dipeptide, interleukin 1, interleukin 2, 16,16 dimethyl PGE2, and the lipoxgenase inhibitor AA861 to potentiate the DST effect singly, 4) to test combinations of effective immunomodulating drugs on the DST effect, and 5) to evaluate the ability of low dose cyclosporine to further augment effective combinations found in the above experiments. Is is anticipated that several protocols will be identified and will result in indefinite survival in the difficult ACI to Lewis graft model. The sixth experiment will determine whether third party blood can be used instead of DSTs for augmentation of the transfusion effect. Finally, the protocols of immunomodulation that worked for rodents will be verified in a canine model. Models which achieve greater than 50% heart allograft survival for longer than 100 days posttransplantation in the ACI to Lewis model will be studied for the mechanisms of immunologic tolerance. Particular emphasis will be placed in the role of prostaglandins and macrophage suppressor mechanisms. Our goal is to establish a model which can be used for clinical transplantation in man that will minimize or perhaps even avoid entirely the necessity for long term immnmosuppression.